Autoimmune diseases are a major cause of morbidity and mortality, afflicting approximately 3-10% of the population in Western countries. There are more than 80 distinct autoimmune diseases, most of which are chronic conditions that often manifest debilitating and life-threatening complications. Current therapies for autoimmune diseases are suboptimal because they often cause generalized immunosuppression, which predisposes the recipient to serious infections and cancer. Moreover, these therapies fail to correct the fundamental biological defect underlying autoimmune disease pathogenesis: loss of immunologic self-tolerance. The outcome of autoantigen recognition by the immune system (self-tolerance or autoimmune disease) is largely determined by the activation state of the dendritic cells (DCs) that uptake, process, and present autoantigens to autoreactive T cells. In particular, activation of dendritic cells to an immunogenic phenotype is necessary for the full activation of naïve autoreactive T cells, and thus necessary for the initiation of autoimmune disease. There is a need for better understanding of the cellular and molecular triggers and mechanisms of DC activation, which could catalyze the development of novel therapies to induce self-tolerance in patients with autoimmune disease.